Dual spatio-functional control of a fission yeast-based bioprocessor upon chemical induction

Abstract

Next-generation therapies are advancing beyond small molecules and proteins toward engineered living microorganisms that interact symbiotically with their host and respond to signals precisely when and where needed. Despite progress in the field, engineering cells to both produce biopharmaceuticals and achieve site-specific recruitment remains a challenge. In this work, we genetically engineered the mating pathway of S. pombe to create a “bioprocessor” that responds to a chemical trigger, an artificial replica of the sexual pheromone of the yeast cells, the P-factor, enabling functional control over the production of Albulin as a proof-of-concept biopharmaceutical. This activation simultaneously induces the expression of hydrophobic agglutinins on the cell surface, modifying surface chemistry and adhesion properties. Exploiting this modification, we could simultaneously implement spatial control, allowing selective adhesion to a hydrophobic target surface. Adhesion control tests confirmed the fundamental role of hydrophobic interactions in this adhesion process, enabling selective cell adherence only after activation with P-factor and expression of the agglutinins, even in presence of potentially interfering cells. This approach represents an important milestone in the development of a straightforward chemically-activated multi-control mechanisms, which enable precise and programmable responses in engineered cells. Such advancements pave the way for a new generation of bio-responsive materials and therapeutic devices, including functional implants and targeted delivery systems, where engineered cells can operate in synergy with host tissues, responding to specific environmental cues to produce therapeutic agents exactly when and where they are needed.